DESCRIPTION: The overall goals of Dr. McIntosh's proposal are to determine the impact on important biological processes of short-and long-range interactions measured between lipid membranes. These interactions include entropic (steric) interactions due to membrane flexibility or motion of individual lipid molecules, and attractive and repulsive interactions caused by oriented dipoles in the membrane. Specific aims include determining: (1) the magnitude and origin of the adhesion energies of selected membrane glycolipids, including galactosyl- and glucosyl-ceramides, (2) the molecular organization and adhesive properties of the specialized ceramide-containing lipid lamellae that comprise the extracellular matrix of the skin stratum corneum, (3) the effects on both bilayer structure and interbilayer repulsive pressures of small peptides and lipophilic molecules that inhibit or promote cell fusion, (4) the influence of entropic pressures and dipolar electric fields on the binding of proteins to lipid membranes, and (5) the mechanism by which custom-designed polyphenolic molecules increase the adhesion between membranes. The research involves the combined use of x-ray and neutron diffraction/osmotic stress measurements of membrane structure and short-range interactions; resonance energy transfer and circular dichroism studies of peptide and protein binding; differential scanning calorimetry , dipole potential, microelectrophoresis, and micropipette analyses of bilayer thermal, electrostatic, and mechanical properties; and direct observations on in vivo extravasation of drug-containing liposomes. This fundamental basic research has several practical biomedical applications, including the development of intravenous and transdermal drug delivery systems and biocompatible coatings for medical implants.